There are three main metabolic pathways utilized by humans to produce energy in the form of adenosine triphosphate (ATP): oxidative respiration, anaerobic glycolysis and the phosphagen system (Lanza I R, Befroy D E, Kent-Braun J A. Age-related changes in ATP-producing pathways in human skeletal muscle in vivo. J Appl Physiol. 2005 November; 99(5):1736-44).
Under conditions where oxygen is available, oxidative respiration in the mitochondria generates ATP. Aerobic metabolism involves a complicated series of reactions to produce energy. In terms of efficiency, aerobic metabolism provides more energy than anaerobic metabolism. Aerobic respiration is used to provide energy during endurance-type activities which are typified by low- to moderate-intensity activities maintained for long durations (Korzeniewski B. Regulation of oxidative phosphorylation in different muscles and various experimental conditions. Biochem J. 2003 Nov. 1;375(Pt 3):799-804).
Anaerobic glycolysis is utilized for energy when aerobic metabolism becomes limiting for ATP production as occurs during strenuous physical activity. Anaerobic metabolism is considerably less efficient than aerobic metabolism, in terms of energy produced. Anaerobic glycolysis is typically needed to produce energy when the oxygen supply to muscle is limited, such as during short duration high-intensity activity (Casey A, Greenhaff P L. Does dietary creatine supplementation play a role in skeletal muscle metabolism and performance? Am J Clin Nutr. 2000 August; 72(2 Suppl):607S-17S).
Phosphoscreatine is the phosphagen utilized by humans to store energy in a form that can quickly be used to regenerate ATP. The enzyme creatine kinase catalyzes a reversible reaction in which phosphocreatine is used as a source of phosphate to regenerate ATP from ADP (adenosine phosphate). Phosphocreatine provides a rapid source of ATP but is very limited, only supplying enough energy for a few seconds of high-intensity activity.
Both aerobic and anaerobic metabolisms share the initial steps of substrate processing, whereby blood glucose or muscle glycogen is converted to pyruvate. In the presence of adequate oxygen pyruvate is then used in the citric acid cycle, also known as the Krebs cycle. Glycolysis can proceed so quickly that pyruvate accumulates in the muscle. When this accumulation of pyruvate occurs, the enzyme lactate dehydrogenase converts pyruvate to lactate (Gladden L B. Lactic acid: New roles in a new millennium. Proc Natl Acad Sci USA. 2001 Jan. 16;98(2):395-7). Lactate, in turn, is used to regenerate nicotinamide adenine dinucleotide (NAD+), an important cofactor needed for glycolysis (Robergs R A, Ghiasvand F, Parker D. Biochemistry of exercise-induced metabolic acidosis. Am J Physiol Regul Integr Comp Physiol. 2004 September; 287(3):R502-16).
Traditionally, Lactic acid has been thought to be a toxic waste product responsible for muscle fatigue, reduced performance and muscle pain following intense exercise. This has largely been due to the coincidental lowered pH associated with intense exercise and increased muscle lactate. As such, this has been termed “lactic acidosis” and has been theorized to be caused by the production of lactic acid, which acidifies or lowers the pH by losing a proton (H+) in bodily tissues and fluids.
A more recent re-interpretation of previous findings in light of new data suggests that lactic acid may in fact not be the cause of the aforementioned exercise-induced metabolic acidosis (Robergs R A, Ghiasvand F, Parker D. Biochemistry of exercise-induced metabolic acidosis. Am J Physiol Regul Integr Comp Physiol. 2004 September; 287(3):R502-16). The accumulation of inorganic phosphate and protons, mostly from the hydrolysis of ATP at a rate which exceeds that of ATP regeneration, is supported by evidence to be more likely than lactic acid as the cause of exercise-induced metabolic acidosis.
G. Brooks in an abstract from the 2006 Journal of the International Society of Sports Nutrition Conference Proceeding discloses that the shuttling of lactate through the interstitium and vasculature provides a significant carbon source for oxidation and gluconeogenesis during rest and exercise. Furthermore, adding to the original idea that lactate released from fast glycolytic fibers fuels slow-oxidative fibers, it known now that lactate is shuttled between different cells, organs and tissues to provide an energetic function. Lactate, due to recent evidence is being viewed as an essential component of intermediary metabolism and no longer a metabolic waster product (Brooks G. The Lactate Shuttle. International Society of Sports Nutrition Conference Proceedings. Journal of the International Society of Sports Nutrition. 2006. 3(1)S30-S43).
Therefore, in fact, the cellular presence and production of lactate, or lactic acid, has been suggested to be beneficial for prolonging exercise (Messonnier L, Denis C, Feasson L, Lacour J R. An elevated sarcolemmal lactate (and proton) transport capacity is an advantage during muscle activity in healthy humans. J Appl Physiol. 2006 Jul. 27; [Epub ahead of print]). It should be noted that “lactic acid” does not exist as an acid under normal physiological conditions but rather as a lactate anion. Additionally, not only does the production of lactate assist in the regeneration of NAD+ but it also consumes a proton which buffers against metabolic acidosis, As such, lactate likely does not cause or contribute to metabolic acidosis. Furthermore, lactate has been shown to be a key fuel source and the concept of the “lactate shuttle” has been largely supported by experimental evidence (Brooks G A. Lactate shuttles in nature. Biochem Soc Trans. 2002 April; 30(2):258-64). The term “lactate shuttle” as used herein refers to the transport or “shuttling” of lactate, both intracellularly and intercellularly. One of the main observations has been that endurance/aerobic training reduces blood lactate levels despite the continued production of lactate from muscle cells, thus giving rise to the concept that, against traditional thinking, lactate and the lactate shuttle must contribute as fuel source to working muscles.
The lactate shuttle is facilitated by membrane-bound monocarboxylate transporters (MCTs). In skeletal muscle, two distinct isoforms have been characterized—MCT-1 and MCT-4, each with different properties. Training has been shown to have effects on the expression of MCTs resulting in more efficient use of lactate, particularly with respect to the clearance of lactate from the blood by increasing its uptake within cells (Dubouchaud H, Butterfield G E, Wolfel E E, Bergman B C, Brooks G A. Endurance training, expression, and physiology of LDH, MCT1, and MCT4 in human skeletal muscle. Am J Physiol Endocrinol Metab. 2000 April; 278(4):E571-9).
Most lactate is removed through oxidation while the remainder is converted to glucose and glycogen. The hypothesis of the lactate shuttle holds that excess lactate transported both intracellularly (via an intracellular lactate shuttle) and intercellularly (via a cell-to-cell lactate shuttle) for use as immediate fuel or for storage (Gladden L B. Lactate metabolism: a new paradigm for the third millennium. J Physiol. 2004 Jul. 1;558(Pt 1):5-30). Muscles at rest produce and release low levels of lactate with little uptake. During periods of short duration but high-intensity muscle activity, muscles produce and release higher levels of lactate into the blood. During recovery, or during low- to moderate-intensity activity, muscles show a net increase in the uptake of lactate from the blood. Within cells lactate produced from glycolysis is transported from the cytosol into the mitochondria where it is subsequently converted to pyruvate. As pyruvate, it can be utilized in the citric acid cycle.
As there is a need, it would therefore be advantageous to increase the availability and usage of lactate, either through endogenous mechanisms, or through exogenous sources. By increasing the production of lactate within a cell, the intracellular lactate shuttle may be utilized to supply the cell with increased energy. Moreover, by concomitantly increasing the production and/or secretion of lactate from a given cell and increasing the uptake of lactate by another cell, the cell-to-cell lactate shuttle may be utilized to supply additional, distal cells with increased energy. It would therefore be advantageous to improve the energy supply to muscle and other bodily systems, organs, tissues or cells through enhancing the production and utilization of endogenous fuel sources i.e. lactate, in a mammal.